The broad, long-term objective of this proposal is to develop methods available for complex small molecule organic synthesis on a solid support. The relevance of this objective to health related issues is that with the ability to carry nonpolymeric organic molecule synthesis on a solid support comes the ability to create small organic molecule libraries. Since the molecular weight of most drugs is less than 750, i.e., small organic molecules, the ability to create such libraries holds great promise for expediting the drug discovery process. In this proposal HIV infection is the specific health related issue targeted. The solid phase synthesis of hydroxyethylene peptide isosteres - potential HIV protease inhibitors - will be pursued. The established solution phase synthesis is short, high yielding and amenable to variation at several positions of the isostere. Once the ability to scope carrying out the isostere synthesis on the solid phase is determined, a library of capped isosteres will be synthesized and screened against HIV protease I. A known linker will be used initially as the solid phase chemistry is established. A novel resin-amine linkage will be subsequently pursued which has the advantage of liberating isosteres free of any linker remnants upon cleavage from the resin. The chemistry involved in the isostere synthesis and in the novel linker development will be of general interest, beyond that HIV protease I inhibition, since the synthetic transformations to be studied have little or no precedence of the solid phase.